The complications of myocardial infarction contribute to 550,000 cases of heart failure (HF) and 300,000 cases of sudden cardiac arrest (SCA) annually. HF and SCA are mechanistically linked to the closely related processes of mechanical and electrical remodeling of the heart following infarction. Markers of adverse remodeling are widely used to risk-stratify post-MI patients for medical or device therapies. However, current risk-stratification strategies lack adequate sensitivity and specificity. Thus, development of complementary biomarkers to predict adverse outcomes post-MI is needed for the appropriate and cost-effective applications of these advanced therapies. Cellular micro-RNAs (miRNAs) regulate entire gene networks in human cardiovascular diseases and circulating miRNAs can be used as integrative biomarkers. We now propose to identify novel circulating miRNA signatures that can prognosticate susceptibility to arrhythmia/SCA and HF post-MI and to integrate these biomarkers into a digital PCR-based assay readily translatable into the clinic. Our group of investigators spanning multiple discipline within cardiovascular research will test the central hypothesis that (1) unbiased profiling of circulating plasma using RNA-seq will identify novel miRNAs associated with the development of adverse mechanical and electrical remodeling in a cohort of extensively-phenotyped post-MI patients; (2) mechanistic animal and cell culture models will complement the clinical discovery efforts by helping prioritize those markers that play a functional role in disease pathobiology, and (3) the assessment of miRNA signatures of adverse remodeling will enable accurate prediction of clinical outcomes, notably SCA and HF, in a large cohort of patients with CAD and MI. We believe that our results will lay the foundation for a novel strategy of risk-stratificationfor post-MI patients that would allow for identification of patients at high risk of adverse electrical and mechanical remodeling, who may benefit from more aggressive monitoring and interventions with medications and ICDs.